DESCRIPTION: (Applicant's Abstract) The cholinergic neurons of the basal forebrain (BFCN) within the mammalian brain comprise a large neuronal system with diffuse cortical projections. A substantial body of evidence has shown that these neurons are intimately involved in the processes of learning, memory and attention. Within the human brain, the BFCN are selectively vulnerable in neurodegenerative diseases that afflict the elderly, such as Alzheimer's disease (AD). This age-dependent vulnerability suggests that normal age-related changes contribute to the degeneration of these neurons. Until recently, however, no substantial changes had been reported in the BFCN in the normal aged human brain. In an earlier study, we had observed that the majority of the primate BFCN contain the calcium binding protein Calbindin-D28k (CalBP). More recently, we have discovered that the human BFCN displays a substantial and selective loss of CalBP in the process of normal aging. We hypothesize that the loss of CalBP deprives the BFCN from the ability to buffer intracellular calcium and leaves them vulnerable to neuropathologic processes that increase intracellular calcium and thus lead to degeneration. These studies outlined in the present proposal are aimed at providing information on the role of calbindin in the degeneration of BFCN in aging and disease. The aims of the proposed experiments are to provide more comprehensive information on the age- related loss of CalBP from the human BFCN, to determine the status of CalBP in the BFCN in neurodegenerative disease of the elderly, to investigate the pathological and molecular correlates of this loss; to determine the influence of the loss of CalBP on the degeneration of BFCN in aging and AD, and to investigate animal models in which the neuroprotective role of CalBP in the BFCN can be studied using genetic approaches. The results will have important implications for the depletion of BFCN and the concomitant memory deficit and other cognitive abnormalities in aging and neurological diseases and have the potential to lead to new therapeutic possibilities.